The present invention relates to specific cytokine antagonists which are provided for the treatment and prevention of damage to the optic nerve, other cranial nerves, brain, spinal cord, nerve roots, peripheral nerves or muscles caused by any one of the following: a herniated nucleus pulposus, osteoarthritis, other forms of arthritis, disorders of bone, disease, or trauma. More particularly, the cytokine antagonists are used in a new treatment of these disorders utilizing localized anatomic administration which causes inhibition of the action of the corresponding pro-inflammatory cytokine in a localized anatomic area of the human body. The administration of these cytokine antagonists is performed by anatomically localized administration which includes, but is not limited to the following routes: perilesional; intralesional; and transepithelial (for disorders of the optic nerve). Perilesional routes as mentioned above include, but are not limited to, subcutaneous, intramuscular, and epidural routes of administration.
Localized administration for the treatment of localized clinical disorders has many clinical advantages over the use of conventional systemic treatment. Locally administered medication after delivery diffuses through local capillary, venous, arterial, and lymphatic action to reach the anatomic site of neurologic or muscular dysfunction; or in the case of the eye through the conjunctiva, then through the aqueous and vitreous humor to reach the optic nerve and retina.
All of the cytokine antagonists which are currently available have been developed for systemic administration. This is because all were developed to treat systemic illnesses, including rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, and Crohn""s Disease. Systemic illnesses by definition require systemic treatment.
The use of cytokine antagonists to treat localized disorders is discussed in U.S. Pat. Nos. 6,015,557 and 6,177,077 and other pending applications of the applicant. This invention includes further applications of these ideas.
Localized administration, including perilesional or intralesional administration, when compared to systemic administration, carries with it one or more of the following advantages:
1) greater efficacy due to the achievement of higher local concentration;
2) greater efficacy due to the ability of the administered therapeutic molecule to reach the target tissue without degradation caused by hepatic or systemic circulation;
3) more rapid onset of action;
4) longer duration of action; and
5) Potentially fewer side effects, due to lower required dosage.
Pilot studies conducted by the inventor for one of the disorders discussed herein, herniated nucleus pulposus, have demonstrated the dramatic efficacy, and the extraordinarily rapid onset of action of perilesional administration in this clinical disorder. Ongoing pilot studies for other clinical conditions also demonstrate positive results.
Neurological disorders due to a herniated nucleus pulposus, osteoarthritis, other forms of arthritis, disorders of bone, disease, or trauma causing damage to the optic nerve, other cranial nerves, spinal cord, nerve roots, or peripheral nerves are common and cause considerable morbidity in the general population. Common to all of these disorders is the fact that they can cause permanent neurological damage, that damage can occur rapidly and be irreversible, and that current treatment of these conditions by pharmacologic or other means is often unsatisfactory. Surgical treatment is therefore often required, and is not uniformly successful.
Of these neurological disorders, radiculopathy due to a herniated nucleus pulposus is among the most common. This condition occurs in both the lumbar and cervical regions. Lumbar radiculopathy due to the herniation of a lumbar intervertebral disc causes sciatica i.e. pain in the lower back with radiation to a leg. Neurologic symptoms and signs are often present, including numbness, paresthesia, and motor symptoms involving the leg or foot. Cervical radiculopathy caused by a herniated nucleus pulposus in the cervical region causes pain and neurologic symptoms in the neck and an upper extremity. Other localized neurological conditions include acute spinal cord trauma, spinal cord compression, spinal cord hematoma, cord contusion (these cases are usually traumatic, such as motorcycle accidents or sports injuries); acute or chronic spinal cord compression from cancer (this is usually due to metastases to the spine, such as from prostate, breast or lung cancer); and carpal tunnel syndrome. Localized disorders of the cranial nerves include Bell""s Palsy; and glaucoma, caused by glaucomatous degeneration of the optic nerve.
Pharmacologic agents used in the past to treat these disorders have included corticosteroids. Corticosteroid administration, however, may cause multiple side effects, and is often ineffective.
Newer biopharmaceutical medications have been developed which have been shown to offer dramatic clinical benefit for systemic illnesses in humans, even for those disorders which have not responded to large and repeated doses of corticosteroids. These biopharmaceutical medications fall into the category of cytokine antagonists because they block, or antagonize, the biologic action of a specific cytokine which has adverse clinical effects. These cytokines include members of the interleukin class and tumor necrosis factor.
Tumor necrosis factor (TNF) is intimately involved in the nervous system and in inflammatory disorders of muscle. It is central to the response to injury, either virally induced, disease induced, or occurring as a result of mechanical trauma. TNF is also central to neuronal apoptosis, a process important in many neurological disorders.
Specific inhibitors of TNF, only recently commercially available, now provide the possibility of therapeutic intervention in TNF mediated disorders. These agents have been developed to treat systemic illnesses, and therefore have been developed for systemic administration. Various biopharmaceutical companies have developed TNF antagonists to treat systemic illnesses: Immunex Corporation developed etanercept (Enbrel(copyright)) to treat rheumatoid arthritis; Johnson and Johnson developed infliximab (Remicade(copyright)) to treat Crohn""s Disease and rheumatoid arthritis; D2E7, a human anti-TNF monoclonal antibody (Knoll Pharmaceuticals) is being developed to treat rheumatoid arthritis and Crohn""s Disease; and Ceiltech is developing CDP 571 to treat Crohn""s Disease and CDP 870 to treat rheumatoid arthritis.
Recent research has demonstrated that a new TNF antagonist can be manufactured from an existing molecule by subtracting a portion of the amino acid sequence from the molecule. This has the advantage of making the molecule smaller. This smaller molecule can be easier to manufacture and may have clinical advantages, such as reduced immunogenicity in the human in vivo. Therefore, the molecules of consideration here shall also include, in addition to those specified, any molecule which contains a fragment of any of the named molecules. A fragment shall be defined as an identical amino acid sequence 50% or greater in length of the original molecule and possessing TNF binding capability.
Pharmacologic chemical substances, compounds and agents which are used for the treatment of neurological disorders, trauma, injuries and compression having various organic structures and metabolic functions have been disclosed in the prior art. For example. U.S. Pat. Nos. 5,756,482 and 5,574,022 to ROBERTS et al disclose methods of attenuating physical damage to the nervous system and to the spinal cord after injury using steroid hormones or steroid precursors such as pregnenolone, and pregnenolone sulfate in conjunction with a non-steroidal anti-inflammatory substance such as indomethacin. These prior art patents do not teach the use of specific cytokine antagonists for the suppression and inhibition of the action of IL-1 in the human body to treat neurological disease, trauma, injury or compression, as in the present invention.
U.S. Pat. No. 5,863,769 discloses using IL-1 RA for treating various diseases. However, it does not disclose administering cytokine antagonists locally for the treatment of localized neurological or muscular disorders.
U.S. Pat. No. 6,013,253 discloses using interferon and IL-1 RA for treating multiple sclerosis. However, it does not disclose administering cytokine antagonists locally for the treatment of localized neurological or muscular disorders.
U.S. Pat. No. 5,075,222 discloses the use of IL-1 inhibitors for treatment of various disorders. However, it does not disclose administering cytokine antagonists locally for the treatment of localized neurological or muscular disorders.
PCT Application WO 00/18409 (Apr. 6, 2000) discloses the use of various medications to treat nerve root injury. It does not disclose the methods discussed herein. including localized administration, perilesional administration, or intralesional administration, of the substances discussed herein.
None of the prior art patents disclose or teach the use of localized administration of a cytokine antagonist as in the present invention for suppression and inhibition of the action of a specific cytokine in a human to treat localized neurological or muscular disease, in which the cytokine antagonist provides the patient with a better opportunity to heal, slows disease progression, prevents neurological damage, or otherwise improves the patient""s health.
Accordingly, it is an object of the present invention to provide a cytokine antagonist administered through anatomically localized administration as a new method of pharmacologic treatment of neurological disorders, trauma, injuries and compression affecting the nervous system of the human body; and for treating localized disorders of muscle; such that the use of these cytokine antagonists will result in the amelioration of these conditions.
Another object of the present invention is to provide cytokine antagonists for providing suppression and inhibition of the action of specific cytokines in a human to treat neurological injury, trauma or compression; and localized muscular disorders.
Another object of the present invention is to provide cytokine antagonists that reduce inflammation by inhibiting the action of specific cytokines in the human body for the immediate, short term (acute conditions) and long term (chronic conditions), such that this reduction in inflammation will produce clinical improvement in the patient and will give the patient a better opportunity to heal, slow disease progression, prevent neurological damage, prevent muscular damage, or otherwise improve the patient""s health.
Another object of the present invention is to provide cytokine antagonists, using anatomically localized administration as the preferred form of administration, that offer acute and chronic treatment regimens for neurological conditions caused by neurological trauma, compression, injury and/or disease, such conditions including acute spinal cord injury; herniated nucleus pulposus (herniated disc); other related neurological disorders and diseases; spinal cord compression due to metastatic cancer; Bell""s Palsy; glaucoma and glaucomatous optic nerve degeneration; and muscular disorders.
The present invention provides a method for inhibiting the action of pro-inflammatory cytokines, including TNF, for treating neurological, optic nerve (glaucoma), and muscular disorders in a human by administering to the human therapeutically effective doses of a specific cytokine antagonist directed against one of the aforementioned cytokines for reducing the inflammation of neuronal, optic nerve, or muscular tissue of the human and/or preventing immune system damage to neuronal tissue (including spinal cord, nerve root, cranial nerve, or peripheral nerve) or muscular tissue. The preferred forms of administration are localized anatomic administration, including perilesional, intralesional, or transepithelial (for disorders of the optic nerve) routes. Perilesional routes as mentioned above include, but are not limited to, subcutaneous, intramuscular, and epidural routes of administration.